Crystallization process and device

ABSTRACT

Continuously operated, two-part crystallizer which is particularly suitable for the resolution of racemic mixtures, and process for separating solid mixtures which are difficult to separate, in particular racemates.

The present invention relates to a continuously operated, two-partcrystallizer which is particularly suitable for the resolution ofracemic mixtures, and also a separation process for solids mixtureswhich are difficult to separate, in particular for racemates, using thecrystallizer.

In the synthesis of racemates, the two enantiomers are formed in equalamounts, since they have the same energy content. However, it is oftenthe case that only one of the two stereoisomeric forms is required, forexample, the 1-amino acids for the formation of proteins. It istherefore necessary to separate the racemate into its optically activecomponents, the l and d forms. The crystallization method has, amongother methods, proven useful for the separation of stereoisomers. It isbased on the principle that the desired optically active isomercrystallizes preferentially from a supersaturated solution of theracemate when the solution is seeded with a few crystals of this isomer.Examples of this are the separation of the ammonium salt of acylatedtryptophan and acylated phenylalanine. Derivatives of aromatic sulphonicacids can likewise be separated in this way, e.g. dl-lysine as thesulphanilic acid salt and dl-serine as the m-xylenesulphonate.

To carry out the crystallization process, various types of apparatushave been proposed. U.S. Pat. No. 3,450,751 describes the use of a tubereactor in which backmixing is very largely prevented for the resolutionof racemic glutamic acid, glutamates and their derivatives. Adisadvantage of this process is the necessity of continually having tointroduce seed crystals of the desired enantiomer into thesupersaturated solution of the racemate.

U.S. Pat. No. 3,266,871 proposes the use of a cylindrical vessel whichhas a conical bottom and is divided into two zones by a wire mesh ascrystallizer for the resolution of glutamic acid and its hydrochloride.The mesh opening of the wire mesh is selected such that the seedcrystals cannot get into the other part of the vessel while thesupersaturated racemic solution can, of course, pass through the wiremesh. Each part of the vessel is equipped with a propeller stirrer whichsuspends the seed crystals homogeneously in the respective zone.According to the examples in U.S. Pat. No. 3,266,871, this apparatusgives the following results in the resolution of glutamic acid:

Mean Temper- Duration of Purity of d-Glutamic Exam- residence ature theprocess the l-acid acid ple time (min) (° C.) (h) (%) (%) 1 7.5 50 1092.3 92.5 2 6.0 50 7 96.4 95.6

The optical purity of the seed crystals added was 98%. It is conspicuousthat, at a constant resolution temperature of 50° C., the purity of the1-acid after only 7 hours is only 96.4% and after 10 hours is as low as92.3%. This indicates that although the wire mesh is impermeable to theseed crystals used, it does not present an effective obstacle to verysmall crystal nuclei. This fact is essentially confirmed in the journalChemie-Ing.-Techn. Vol. 42, 1970/No. 9/10, pp. 641-644, according towhich the industrial resolution of the salt of dl-glutamic acid iscarried out at 55° C. in a comparable arrangement and is interruptedafter seven hours: the crystals (whose optical purity is at least 95%)are separated off, new seed crystals are added and the entire procedureis repeated. The arrangement thus does not make a genuine continuousprocess possible, since the crystallized material is regularly replacedcompletely by new seed crystals at relatively short time intervals.

The contamination of the desired enantiomer with crystals of its mirrorimage could be prevented if the two ideally mixed zones are completelyseparated from one another, i.e. if two separate stirred vessels areused. However, the question then arises, as to how the racemic solutiongets from vessel to vessel without carrying crystals with it.

A solution to this problem is described, by way of example, for theresolution α-methyl-3,4-dihydroxy-phenylalanine (α-methyl DOPA) in thejournal Chemical Engineering, Nov. 8, 1965, pp. 247-248. According tothis publication, two stirred vessels are operated in parallel and equalamounts of the supersaturated racemic solution are fed to each. Eachvessel is equipped with a suspension pump which conveys the crystalsuspension through a special filter. In this motor-driven filter, thefiltrate is separated off and returned to the dissolution vessel forenrichment. The thickened suspension flows back into the respectivecrystallizer.

The disadvantage of this apparatus is finding a suitable filter forseparating the filtrate from the crystals. Since no known filter meetsthe requirements, the authors of the abovementioned article have built aspecial filter themselves; however, the abovementioned article gives nofurther details as to the nature of this filter.

U.S. Pat No. 3,892,539 attempts to solve the indicated separationproblem for enantiomers by carrying out the selective crystallization influidized beds. These consist of a lower part which has a conicalconfiguration and tapers towards the bottom and an upper part which iscylindrical. At the bottom end of the fluidized bed there is anultrasonic device which breaks up large crystals which settle out. Forthe resolution of racemic mixtures, preference is given to connectingtwo fluidized beds in series. The supersaturated racemic solution entersthe bottom of the first fluidized-bed crystallizer which is providedwith seed crystals of one enantiomer. The seed crystals grow and,depending on their size and the flow velocity of the solution, assume aparticular vertical position in the crystallizer. The smallest crystalsform a boundary layer in the lower part of the cylindrical bed. In thisregion, site glasses are provided at various heights of the column, thusenabling the position of the boundary layer to be observed and, based onthis, the removal of crystals to be carried out when appropriate. Thesolution which has been depleted in the respective enantiomer andenriched with the opposite enantiomer leaves the cylindrical fluidizedbed at the top and flows to the second fluidized-bed crystallizerarranged downstream.

In the apparatus described, filtration of the solution leaving the firstfluidized bed can be omitted provided that, in particular, sedimentationof the smallest nuclei in the upper part of the fluidized bed (above theboundary layer of the crystals) is 100% effective. The flow velocity ofthe solution keeps the smallest seed crystals in suspension in the lowerregion of the cylindrical fluidized bed; there is therefore a risk thatthe significantly smaller crystal nuclei will be carried out at the sameflow velocity. Furthermore, the apparatus described in U.S. Pat. No.3,892,539 has the considerable disadvantage that it is not reallypossible to change the throughput during operation of the apparatus,because this is associated with an appreciable change in the position ofthe microcrystal boundary layer.

This makes steady-state operation of the crystallization apparatusconsiderably more difficult.

It is an object of the invention to develop a crystallization apparatuswhich should make genuine continuous operation for weeks and monthspossible and does not have the abovementioned disadvantages.

The seed crystals of one enantiomer should be added only once at thebeginning of the production cycle.

The solids concentration should be kept as high as possible in order toachieve (at very low supersaturation) a high space-time yield.

However, the mixing of the solids suspension should nevertheless behomogeneous, i.e. all volume elements of the suspension should have thesame particle size distribution.

The crystals obtainable from the crystallizer should be sufficientlylarge for them to be separated off readily by mechanical means.

The supersaturated feed solution of the enantiomers should be mixed asquickly as possible with the overall solids suspension so that thesupersaturation is quickly reduced.

The solution enriched in one enantiomer should flow from thecrystallization apparatus as a clear solution without carrying with itthe solid phase of the respective enantiomer, not even in the form offine nuclei, so as to avoid poisoning of the crystallizers for a verylong period of time.

The purity of the individual components obtained from the crystallizershould, if possible, be greater than 99%.

The throughput of solution to be resolved should be able to be variedgreatly within wide limits (±30%) without particular modifications ofthe apparatus being necessary.

This object is achieved according to the invention by a crystallizationapparatus which is subject-matter of the invention and is suitable, inparticular, for the crystallization of solids which are difficult toseparate, preferably for the resolution of racemic mixtures, from theirsolutions, comprising an upper part and a lower part, with a heatableand coolable stirred vessel as lower part which has an agitator,optionally a feed line for the crystallization solution and optionally adischarge line for the suspension of the crystallized product, and witha conical, heatable and coolable sedimentation section as upper partwhich has a stirring element running around the wall, optionally adischarge line for the solution depleted in the product and an openingto the stirred vessel, where the agitator generates, in the region ofthe opening, flow of the crystallization solution directed away from theopening.

The agitator is preferably a radial-flow agitator, in particular animpeller stirrer driven from below, a straight-arm stirrer, aflat-paddle stirrer or a CBT turbine. The agitator can also be anaxial-flow agitator which is arranged in a guide tube below the opening.

The axial-flow agitator is, in particular, installed on the central axisof the stirred vessel in order to generate the flow directed away fromthe opening.

The stirring element running around the wall is, in particular, aslow-running blade stirrer which is driven from above and preferably hasan additional frame which wipes across the inner wall of thesedimentation section and thereby keeps it free of deposited crystals.

In a particular embodiment of the invention, the stirring elementsrunning around the wall is designed so as to be heatable or coolable,for example by means of electric resistance heating or with the aid of asystem for passing a heat-transfer medium through it.

In the preferred embodiment, the cone widening towards the top of thesedimentation section has an opening angle of from 10 to 60°, inparticular from 20 to 50°, preferably from 25 to 45°.

The sedimentation section and the stirred vessel are preferably providedwith an additional temperature-control facility which makes it possibleto set the temperature of the reactor contents. Thus, the sedimentationsection or the stirred vessel can have a double wall with feed anddischarge lines for a heat-transfer medium which is passed throughwithin the double wall for cooling or heating the crystallizationsolution.

In a further, preferred variant, the stirred vessel is provided with anadditional pumped circulation loop with heat exchanger which makes itpossible to take a substream of the crystal suspension from theintensively stirred stirred vessel via the pumped circulation loop, toheat it by preferably from 0.1 to 5° C. in the heat exchanger andsubsequently to return it to the stirred vessel.

Since internal fittings for directing the flow can in many cases not beused because of the risk of deposits of solid, the agitator selected forthe stirred vessel is preferably one which generates a high circulationrate even without guide plates. Such an agitator is the impeller stirrerwhich is arranged at the bottom of the stirred vessel and generatesupward flow in the vicinity of the preferably cylindrical wall of thevessel.

In a particularly preferred embodiment of the invention, the flow of thecrystallization solution turns toward the middle of the vessel after adistance of, for example, about one vessel diameter and then flowsvertically downwards in the vessel below the opening to thesedimentation section. In the vicinity of the bottom, the central,primarily axial downward flow is then accelerated radially by theimpeller stirrer and forced upwards by the contour the curved bottom.This generates strong circulation which is very pronounced even in thecase of relatively viscous crystal slurries.

The deflection of the flow by 180° in the upper region of the stirredvessel is reinforced by appropriate shaping of the lid of the stirredvessel and the sedimentation section is joined on in this central regionof the flow directed axially downwards.

The sedimentation section of the apparatus is advantageously conical andits point forms the connection to the intensively stirred crystal slurryzone. So that the turbulence of the crystal slurry is not propagatedinto the sedimentation section, the region where the sedimentationsection and the stirred vessel are joined is provided with aslow-running stirring element, e.g. a four-bladed blade stirrer whichbreaks the secondary flow of the crystal slurry (the rotation). Thepreferred blade stirrer is, in particular, borne by a frame which hasthe conical contour of the sedimentation zone and can be heated orcooled. The stirring element which runs around the wall, e.g. the frameincluding blade stirrer, is slowly turned like a rabbling device (e.g.by a few revolutions per hour) in order to return the solid which hasdeposited on the conical surface to the crystallization zone. This makesit possible, despite an intensively stirred crystallization zone, tojoin on a sedimentation zone in the sedimentation section which isvirtually uninfluenced thereby and from which the desired clear solutioncan be taken off at the top of the sedimentation section withoutinterfering crystal nuclei.

Owing to the sometimes very great differences between the rotationalspeeds of the agitator and the rabbling device, it is particularlyappropriate to choose two drives and to drive the agitator from below.This has the advantage that there is no long shaft rotating in thecrystallization zone of the stirred vessel, which could possibly besubject to caking.

Furthermore, the use of a bottom drive gives quieter running. It is ofcourse also possible to have a variable-speed drive for the agitator soas to take account of changes in the operating conditions (for example achange in the solids concentration or the desired mean particle size ofthe crystals).

The new crystallizer can be advantageously used for the continuousresolution of racemic mixtures, using one crystallizer for eachcomponent of the racemate. These can be connected in parallel or inseries.

The invention also provides a process for separating enantiomers of aracemic mixture using the crystallization apparatus of the invention,which process is characterized in that a supersaturated solution of theracemate is fed to the stirred vessel and is intensively mixed with seedcrystals of one enantiomer by means of the agitator, the flow of theresulting suspension is calmed with the aid of a slow-turning stirringelement which runs around the wall in the sedimentation section and anyfurther product crystals formed on the inner wall of the sedimentationsection are removed and the solution depleted in the enantiomer isdischarged at the top of the sedimentation section.

In a preferred process, two or more crystallization apparatuses of theinvention are connected in series or in parallel and are operatedcontinuously.

In particular, when two crystallization apparatuses are connected inseries, the discharge line of the first crystallization apparatus isconnected to the feed line of the second crystallization apparatus anddifferent seed crystals of the opposite enantiomers are used in the twoapparatuses.

When the apparatuses are connected in parallel, advantages which becomeapparent are not only the high space-time yield of the crystallizationbut also, in particular, the great reliability of the maintenance-freeseparation apparatus (compared with, for example, the special filtersemployed in the prior art), so that the separation process does not haveto be interrupted because of difficulties with suspension pumps or, forexample, filters. However, the particular strength of the crystallizer,namely the absolutely clear solution output, is brought to bear evenmore effectively when the crystallizers are connected in series. In thispreferred process variant, the solution which has been depleted in oneoptically active component and enriched with the other component flowsfrom the first crystallizer via a heat exchanger to the secondcrystallizer. There, poisoning would be caused immediately ifcrystallization nuclei from the first crystallizer had been carried intothe second. The purity of the products obtained and the duration of theproduction process are therefore an index of the quality of solidsseparation.

The ratio of solid crystals to total suspension can be 5-85% by weight,preferably 15-70% by weight, particularly preferably 20-65% by weight.

The invention also provides for the use of the apparatus of theinvention for resolving racemic mixtures by means of crystallization.

As regards the purity of the products, it may be mentioned that, forexample, a purity of better than 99.9% has been achieved in theindustrial resolution of d,l-menthol esters in two crystallizersaccording to the invention connected in series, and the production timewas 6-8 months.

The invention is illustrated below by way of example with the aid of thefigures.

FIG. 1 shows an illustrative embodiment of the crystallization apparatusof the invention.

FIG. 2 shows a cross section through the stirred vessel 1 along the lineA-A′ in FIG. 1.

FIG. 3 shows a cross section through the sedimentation section 2 alongthe line B-B′ in FIG. 1.

FIGS. 4a-4 e show different types of radial-flow stirrers which can beused in place of the preferred impeller stirrer.

FIG. 5 shows an embodiment of the apparatus with a combination of guidetube and axial-flow stirrer.

FIG. 6 shows a series arrangement of two crystallization apparatuses.

FIG. 7 shows a parallel arrangement of two crystallization apparatuses.

EXAMPLE

The crystallization apparatus has two zones: the crystallization zone inthe stirred vessel 1 and the sedimentation zone in the sedimentationsection 2. The stirred vessel 1 is formed by the curved bottom 3, thecylindrical wall 4 and the lid 5 which is shaped so that it aids thedeflection of the upward flow by 180° (see FIG. 1). The circulation ofthe crystal slurry (crystal suspension) in the crystallization zone 1is, as shown in FIG. 1, effected by the impeller stirrer 6 which isarranged in the curved bottom 3 and is driven from below (the drive isnot shown).

In place of the impeller stirrer, the following types of stirrers can beused: straight-arm stirrers (FIG. 4a, 4 b, 4 c), flat-paddle stirrers(FIG. 4d) or a CBT turbine (FIG. 4e).

FIG. 5 shows a variant of the apparatus shown in FIG. 1, in which theimpeller stirrer 6 is replaced by an axial-flow stirrer 22 which islocated within a guide tube 21, thus achieving the desired circulationof the crystal suspension.

The sedimentation section 2 is formed by the wall of the truncated cone7 and the lid 8. Sedimentation section 2 and stirred vessel 1 have adouble wall 16, 17 which makes it possible for a heat-transfer medium toflow through the space in-between. The connections and the heatexchanger are not shown. The opening angle of the truncated cone isabout 30°. So that the solid particles which settle out here do notcollect on the inclined inner wall of the cone 7 but are returned to thecrystal slurry in the stirred vessel 1, the heatable frame 9 which runsaround the wall rotates in the sedimentation section at a very slowspeed (a few revolutions per hour); it is driven from above via theshaft 15 (the drive is not shown). To control the temperature of theframe 9, the feed line 19 and the discharge line 20 provide forheat-transfer medium to flow through the hollow frame 9. In the lowerpart of the truncated cone 7, the four-bladed blade stirrer 10 isintegrated into the frame 9 and prevents transmission of turbulence androtational flow generated by the impeller stirrer to the sedimentationzone in the sedimentation section 2. The axial dimensions of thestirring blades should preferably be greater than the radius of theinlet opening 18 into the sedimentation section 2, particularlypreferably from 1.5 to 2.5 times the radius. In steady-state operation,the crystal suspension goes through the opening 18 into the lower partof the truncated cone 7 and forms a boundary 11 to the crystal-freephase above it. This boundary is relatively insensitive to changes inthe speed of the impeller stirrer and to changes in throughput. Aprerequisite is that the narrowest cross section of the truncated coneat the transition from the crystallization to the sedimentation zone iscorrectly dimensioned for the design throughput. Since many parametersinfluence the position of the crystal boundary 11, e.g. the solidsconcentration, the particle size distribution, the shape of thecrystals, the density difference between the solid and the solution, theintensity of stirring in the crystallization zone and the velocity ofthe solution, it is not possible to give a simple method for calculatingthe narrowest cross section. However, a rough estimate of the crosssection required can be derived from equality of the settling velocityof the smallest crystal particles and the velocity of the solution.

The inlet 12 for the supersaturated solution feed is located in thevicinity of the circumference of the impeller stirrer, the outlet 13 forthe clear solution is located at the top 8 of the sedimentation section2. The suspension containing the crystals produced is taken from thecirculated crystal slurry at distance line 14 and is conveyed tomechanical separation (sieve or centrifuge).

FIG. 6 schematically shows two crystallizers A and B connected inseries. Starting racemate is fed into the circuit at 30. Otherwise, thereference numerals with the suffix A or B in each case denote the sameelements as in FIG. 1. One racemate component is discharged at 14A andthe other racemate component is discharged at 14B.

FIG. 7 schematically shows two crystallizers connected in parallel.

To extend the operating time of the crystallizer, a substream of thesuspension can be taken from the intensively stirred zone 1 via a pumpedcircuit (31A or 31B in FIG. 6), heated by from 0.1 to 5° C. in a heatexchanger and returned to zone 1. This measure has been found to be veryadvantageous since it significantly increases the running time of thecrystallizer.

Although a relatively large volume has to be provided for solidsseparation by sedimentation and this large volume is virtuallycrystal-free, it has been found in operation that no undesired crystalsprecipitate despite the long residence time of the solution in thesedimentation zone.

The continuous separation of l- and d-menthyl benzoate was carried outwith the aid of the crystallization apparatus described, using twocrystallizers according to the invention connected in series.

Two 60 m³ crystallizers of the design according to the invention (cf.FIG. 1) are used for continuous production of 300 kg/h of l- andd-menthyl benzoate. Firstly, the crystallizers are charged with asaturated solution of the racemate of dl-menthyl benzoate in methanol.This solution is then cooled to a temperature which is 0.5° C. below thesaturation point. The two crystallizers are then, with pumps and bladestirrer switched off but with impeller stirrer running, each seeded with500 kg of d- or l-menthyl benzoate crystals. The blade stirrer is thenalso switched on and both crystallizers are flooded with stirrersrunning, with each crystallizer first being operated independently usingan external pumped circuit. In this state, the temperatures in the twocrystallizers are lowered in such a way that the temperature differencebetween inlet 12 and outlet 13 for the solution does not exceed 0.2-0.3°C. When the specific rotation of the clear solution above the crystalshas reached 0°, the two crystallizers are connected in series, i.e. theclear solution enriched in l-menthyl benzoate taken from the firstcrystallizer at outlet 13 is fed to the second crystallizer via itsinlet 12. The solution leaving the second crystallizer at its outlet 13is replenished with dl-menthyl benzoate and returned to the firstcrystallizer. The solution subsequently running from the crystallizershas a specific rotation which is opposite to that of the crystalspresent in the respective crystallizer. The amounts of materialcrystallized out are metered into the circuit as liquid dl-menthylbenzoate. The amount produced is calculated from the difference in thespecific rotation of the solution between inlet and outlet of therespective crystallizer.

The suspension containing the crystals produced is taken from thestirred vessel 1 at the outlet 14 and conveyed to mechanical separation(sieve or centrifuge).

The depleted solution is returned to the reactor after mixing with freshstarting solution.

The quality of the crystals produced is monitored. If the purity dropsbelow 99.6%, the continuous flow through the crystallizers is brieflyinterrupted, and the temperatures in the crystallizers are increaseduntil the rotation of the solution has the same sign as the crystalspresent in the respective crystallizer. The crystallizers are thencooled again until the specific rotation is 0°. The crystallizers arethen again fed continuously with solution so that production iscontinued. During production, about 2-3 tonnes of crystals are presentin the intensively stirred crystallization zone of the crystallizers.After initially seeding once, production can be carried out in theabove-described manner for about 6-8 months.

What is claimed is:
 1. A crystallization apparatus for thecrystallization of solids from their solutions, comprising an upper part(2) and a lower part (1) having a heatable and coolable stirred vessel(1) with an agitator (6), optionally a feed line (12) for thecrystallization solution and optionally a discharge line (14) for thesuspension of the crystallized product, as the lower part and a conical,heatable and coolable sedimentation section (2) having a stirringelement (9, 10) running around the wall, optionally a discharge line(13) for the solution depleted in product and an opening (18) to thestirred vessel (1), as the upper part wherein the agitator (6)generates, in the region of the opening (18), a flow of thecrystallization solution directed away from the opening (18).
 2. Anapparatus according to claim 1, wherein the agitator (6) is aradial-flow agitator, driven from below.
 3. An apparatus according toclaim 1, wherein the agitator (22) is an axial-flow agitator which isdriven from below and is located in a guide tube (21).
 4. An apparatusas claimed according to claim 1, wherein the stirring element (9, 10)running around the wall is a slow-running blade stirrer (10) driven frombelow.
 5. An apparatus according to claim 4, wherein the blade stirrer(10) has an additional frame (9) which keeps the inner wall of thesedimentation section (2) free of crystals.
 6. An apparatus according toclaim 5, wherein the frame (9) is heatable or coolable.
 7. Apparatusaccording to claim 1, wherein the cone of the sedimentation section (2)has an opening angle of from 10 to 60°.
 8. Apparatus according to claim1, wherein the sedimentation section (2), the stirred vessel (1) or bothhas a double wall (7, 17) or (4, 16) through the interior of which aheat-transfer medium is passed for cooling or heating thecrystallization solution.
 9. An apparatus according to claims 1, whereinthe stirred vessel (1) is provided with an additional pumped circulationloop with heat exchanger.
 10. Process for separating enantiomers of aracemic mixture using a crystallization apparatus comprising an upperpart (2) and a lower part (1), having a heatable and coolable stirredvessel with an agitator (6), optionally a feed line (12) for a solutionof the racemic mixture and optionally a discharge line (14) for asuspension of crystallized product as the lower part and a conical,heatable and coolable sedimentation section having a stirring element(9,10) running around the wall, optionally a discharge line (13) fordepleted solution and an opening (18) to the stirred vessel, as theupper part, wherein the agitator (6) generates, in the region of theopening (18), a flow of solution directed away from the opening (18),wherein a supersaturated solution of the racemate is fed to the stirredvessel and is intensively mixed with seed crystals of one enantiomer bymeans of the agitator (6), the flow of the resulting suspension iscalmed in the sedimentation section (2) with the aid of the slow-turningelement (9,10) running around the wall and any further product crystalsformed on the inner wall of the sedimentation section are removed andthe solution depleted in the enantiomer is discharged at the top of thesedimentation section.
 11. Process according to claim 10, wherein two ormore crystallization apparatuses are connected in series and areoperated continuously.
 12. Process according to claim 11, wherein thedischarge line (13) of the first crystallization apparatus is connectedto the feed line (12) of the next crystallization apparatus anddifferent seed crystals of the opposite enantiomers are used in the twoapparatuses.
 13. Process according to claim 10, wherein two or morecrystallization apparatuses are connected in parallel and are operatedcontinuously.
 14. Process according to claim 10, wherein a substream ofthe suspension is taken from the intensively stirred stirred vessel (1)via an additional pumped circulation loop with heat exchanger, heated by0.1-5° C. in the heat exchanger and returned to the stirred vessel (1).15. A method for resolving racemic mixtures, which comprises separatingthe isomers of said racemic mixtures by crystallization in the apparatusof claim 1.